PROJECT 1. EARLY TREATMENT RESEARCH PROJECT: Circulating Reservoirs While current antiretroviral therapy (ART) can effectively suppress HIV replication and prolong life of infected individuals, the virus persists in a latent state, only to re-emerge when ART is stopped. Without biomarkers that can accurately and consistently predict either time to viral rebound after ART discontinuation, the assessment of HIV remission will require the interruption of ART. Our Revealing Reservoirs during Rebound (R3) program will take the next steps in finding a cure for HIV by understanding how HIV persists in and populates reservoirs throughout the body. Studying people treated early after their infection who have a more preserved immune system offer a unique opportunity to reveal HIV reservoirs, especially reservoirs in circulating CD4+ T cell subsets. The Early Treatment Research Project (RP) will maximize data and samples collected from previous and ongoing ART interruption studies to determine: Aim 1: Virologic and immunologic quantities measured during ART that predict dynamics of viral rebound when ART is stopped; Aim 2: Dynamics of HIV rebounding variants populating CD4+ T cell subsets after ART interruption and decaying in subsets after re-suppression. Aim 3: Immunologic mechanisms associated with HIV persistence during ART and after ART interruption. To address these open questions, this RP will analyze data currently available from over 500 people who started ART during acute and early HIV infection and then interrupted this therapy under monitored conditions. To complement these available data, this RP will also generate and analyze longitudinally collected virologic, genetic and immunologic data from two cohorts (n=90 total) of HIV-infected individuals who also started ART during acute and early infection and then interrupted this therapy. Altogether, this RP will create considerable new knowledge about how HIV resides in circulating reservoirs, but the circulating HIV reservoir is only a part of the total full-body HIV reservoir, therefore, the insights gained in the Early Treatment RP will be investigated in conjunction with the data generated in the Late Treatment RP, which is designed to investigate the full body reservoirs. Data from both of these RP be used to develop and evaluate new analytical methods with the Quantitative Methods RP to more fully understand HIV dynamics throughout the body.